The present invention generally relates to CoQ-10/cyclodextrin complexes and more particularly to one that is in a highly bioavailable form.
Cyclodextrins are cyclic oligosaccharides composed of 6, 7, or 8 α-(1-4)-linked anhydroglucose units. The α-, β-, and γ-cyclodextrins prepared from starch are considered natural and are GRAS according to the USFDA. Several chemically modified forms, such as, methyl, dimethyl, and hydroxypropyl-cyclodextrins have been developed.
Coenzyme Q-10 (ubiquinone or CoQ-10) is a strongly lipophilic molecule, insoluble in aqueous solution and having poor bioavailability in humans. CoQ-10 has therapeutic effects in several disease conditions, such as, for example, cardiovascular disease, periodontal diseases (U.S. Pat. No. 6,461,593), high blood pressure, and Parkinson's disease. Hence, several attempts have been made to improve its bioavailability using emulsifying agents, surfactants, and oil-based vehicles which solubilize CoQ-10. Since CoQ-10 is a lipophilic molecule, micellarizarion and transfer to the aqueous phase is necessary for intestinal absorption. Formulations containing a fully solubilized form of CoQ-10 facilitate incorporation of CoQ-10 into the micellar phase. One of the disadvantages of such formulations is the limited solubility of CoQ-10 in oil or surfactant mixtures. Incorporation of therapeutic concentrations of CoQ-10 in the nutritional supplements may not be feasible for the manufacturer or economical for the consumer.
It is known in the art that there is a deficiency of CoQ-10 in diseased gingival tissue and that correction of the deficiency improves the mechanisms of immune system in the cells. CoQ-10 dissolved in vegetable oil or in a mixture of surfactants has been proposed for oral care applications. The soluble CoQ-10 has been incorporated into, inter alia, tooth pastes, mouthwashes, or lozenges. Such solubilized forms of CoQ-10 present several problems in oral care formulations. The oily nature of the CoQ-10 solubilized in vegetable oils limits its usage in oral care products, such as mouthwash or toothpaste. The formulation may become unstable with phase separation or the oily aftertaste may create adverse consumer reaction. CoQ-10 dissolved in surfactant mixtures again has limitations in terms of usage. Higher levels of surfactant mixtures can destabilize the oral care formulations. Hence, incorporation of therapeutic levels of CoQ-10 using such solubilized forms may not be commercially feasible.
Complexation of CoQ-10 with cyclodextrins has been tried by a few investigators to improve the dissolution properties and stability of the compound. However, most of the studies use chemically modified cyclodextrins, especially methyl and dimethyl β-cyclodextrins. For example, Japanese Patent JP59047202 describes complexation with methyl β-cyclodextrin with improved solubility for oral or parenteral administration. The publication by Ueno et al. (1989) describes improvement in the dissolution and absorption of CoQ-10 by complexation with dimethyl β-cyclodextrin.
However, these publications do not indicate as to whether complexation with natural cyclodextrins, such as γ- or β-cyclodextrin, will improve the cellular uptake of CoQ-10. It is well known in the art that complexation with different cyclodextrins results in products with varying properties. For example, dimethyl β-cyclodextrin was reported to dramatically enhance the absorption of insulin, while hydroxypropyl β-cyclodextrin had no significant effect (Shao et al., 1994). Based on the solubility profile of the natural cyclodextrins, complexes with β-cyclodextrin are generally less soluble as compared to the γ-cyclodextrin complexes.
Some of the drawbacks of using chemically modified cyclodextrins include, inter alia, unexpected changes in the solubility behavior, safety issues, and commercial availability. For example, dimethyl β-cyclodextrin precipitates out of solution as the temperature is raised to 55° C. It also is reported to exert a detergent-like effect on the biological membranes. In a study determining the intestinal safety of water-soluble α-cyclodextrin derivatives using a Caco2 intestinal cell model, dimethyl β-cyclodextrin showed a dose dependent cytotoxicity (Totterman et al., 1997). In the same model, maltosyl-α-cyclodextrin was less toxic as compared to α-cyclodextrin, while maltosyl β-cyclodextrin and β-cyclodextrin showed similar effects. γ-Cyclodextrin showed the least effect even at a relatively high concentration of 150 mM (Ono et al., 2001).
Complexation of natural cyclodextrins with CoQ10 has been reported in the art. In a series of publications Lutka and Pawlaczyk (1995; 1996a,b; 1997) have described preparing the complexes using a kneading method or a heating method. Both the methods have several disadvantages for scale-up and commercial production.
Japanese patent No. JP56109590 describes complexation with β- and γ-cyclodextrins and drying the complex under reduced pressure. U.S. Patent Application Publication No. 2003/0012774 A1 describes a method of producing the γ-cyclodextrin complex by homogenization/micronization and energy input. The complex is dried in the oven at 55° C. The published application, however, does not explore the effects of drying the complex to determine a suitable commercial method for large-scale production. It is well known that drying methods, such as spray drying, freeze drying, or vacuum drying, can affect the final yield, stability of the active component, and dissolution properties of the product. Also, none of these publications have any information on the effects of complexation on the absorption of CoQ-10 from the cyclodextrin complexes either in vitro or in vivo. JP60089442 reports an aqueous complex of CoQ-10 and γ-cyclodextrin that is said to have sustained release after gastric administration. Cyclodextrin/CoQ-10 complexes for skin preparations are reported in EP 1174109 (2002). Skin care products containing combinations of biotin, ubiquinone, and cyclodextrins (including γ-cyclodextrin) are reported in DE10139851 (WO203026603).